This section includes a series of clinical studies aimed to test hypotheses concerning opiate dependence and withdrawal generated by the preclinical work in Projects 1-3. The proposed program of research will examine: l) spontaneous opiate withdrawal in clinical opiate detoxification studies, and 2) naloxone-precipitated opiate withdrawal in a repeated challenge paradigm. The excitatory amino acid contribution to opiate withdrawal will be studied initially with dextromethorphan, a widely used non-opioid antitussive which inhibits excitatory amino acid neurotransmission in pre-clinical studies, and has shown pilot efficacy for the treatment of opiate withdrawal. Based on preclinical findings of altered calcium-channel concentration and calcium-linked neurotransmission in rat brain during opiate dependence, we will study the anti-withdrawal efficacy of nimodipine, a centrally-acting calcium channel blocker which has shown promise in pilot studies. An alternative approach to opiate detoxification will test whether repeated administration of the alpha-2 adrenergic antagonist yohimbine to methadone-dependent patients attenuates the severity of opiate withdrawal when methadone is discontinued, as suggested by a recent study in laboratory animals conducted by our preclinical group.